Prostate cancer is the most common type of cancer found in men and the second leading cause of cancer deaths in Western countries. Chromosomal rearrangements and extensive copy number alterations are prevalent in prostate cancer, whereas point mutations are relatively rare6,7,8. Chromosomal rearrangements occur in a coordinated fashion by a phenomenon termed chromoplexy1. Chromoplectic tumors are characterized by presence of the TMPRSS2-ERG gene fusion and expression of a functional chromatin-remodelling enzyme CHD11,2. Recent data suggest that CHD1 is directly involved in TMPRSS-ERG fusion and that the chromosomal rearrangements resulting in the generation of TMPRSS-ERG fusion are coupled to androgen receptor (AR)-dependent transcription9.
In recent years, LSD1 was identified as a potential target for prostate cancer therapy10,11,12. LSD1 is a histone demethylase that removes mono- and dimethyl marks from either lysine 4 or lysine 9 of histone 3 (H3)10,13. When associated with AR, the enzyme removes repressive methyl marks from H3K9, thereby enhancing AR-dependent gene transcription and prostate tumor cell proliferation10.
There is the need for compounds which block the AR-dependent gene transcription and can thus be used in prostate tumor therapy. It is of course highly desirable that these compounds are as selective as possible in order not to interfere with further signal transduction pathways in the cells. Screening methods for such compounds are of course also of high interest.
LSD1 is not only implicated in prostate cancer but also in carcinogenesis and in maintenance of the malignant state in various other cancers. Thus, besides prostate cancer, a role for LSD1 has also been described breast cancer (see e.g. Lim et al., Carcinogenesis. 2010 March; 31(3): 512-20), colon cancer (see e.g. Huang et al., Clin Cancer Res. 2009; 15:7217-7228) and neuroblastoma (see e.g. Schulte et al., Cancer Res. 2009 Mar. 1; 69(5): 2065-71). Further, overexpression of LSD1 has been implicated in carcinogenesis of bladder, lung and colorectal cancer (see e.g. Hayami et al., Int J Cancer. 2011 Feb. 1; 128(3): 574-86) and a role for LSD1 in the self-renewal of leukemic stem cells in acute myeloid leukemia (AML) has been described (see e.g. Mould et al., Med Res Rev 2014 Nov. 24 doi: 10.1002/med.21334, wherein inhibitors of LSD1 for the treatment of AML are also disclosed).
There is of course also an ongoing need for novel compounds for use in therapy of these cancer types. Again, it is highly desirable that these compounds are as selective as possible in order not to interfere with further signal transduction pathways in the cells. Screening methods for such compounds to be used in the therapy of other cancer types are of course also of high interest.